Combinations of Eszopiclone and Trans 4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-N-Methyl-1-Napthalenamine or Trans 4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-1-Napthalenamine, and Methods of Treatment of Menopause and Mood, Anxiety, and Cognitive Disorders

ABSTRACT

One aspect of the present invention relates to pharmaceutical compositions containing two or more active agents that when taken together can be used to treat, e.g., menopause, mood disorders, anxiety disorders, or cognitive disorders. The first component of the pharmaceutical composition is a sedative eszopiclone. The second component of the pharmaceutical composition is trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine. The present invention also relates to a method of treating menopause, perimenopause, mood disorders, anxiety disorders, and cognitive disorders.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for thetreatment of menopause and mood, anxiety, and cognitive disorders.

BACKGROUND OF THE INVENTION

Menopause, which is caused by a lowering of the production of female sexhormones that typically occurs at around age 50, but can occur at muchearlier or later ages, can generate disorders such as edema, hot flushes(or flashes), attacks of sweating, muscle and possibly joint pain, sleepdisturbances, dysphoria, nervousness, mood swings, headache,palpitations (enhanced frequency of heart rate), dry mucous membranes,pain during intercourse and urinary disturbances. Hot flashes orflushing are characterized by a sudden onset of warmth in the face andneck, often progressing to the chest. Episodes generally last severalminutes and are evidenced by a visible flushing of the skin. Often suchepisodes are accompanied by sweating, dizziness, nausea, palpitationsand diaphoresis. Such symptoms can disrupt sleep and interfere withquality of life.

Although the cause of hot flashes is not completely understood, they arethought to be a disorder of thermoregulation within the hypothalamusthat is a consequence of declining estrogen levels. The administrationof female sex hormones, such as estrogen, is effective in palliatingthese symptoms, but hormone therapy is fraught with undesirable sideeffects. Four out of five women have disturbing menopause disorders forat least one year and 25% of women have menopause disorders for morethan 5 years. Half of all women have severe disorders. Men may also havehot flashes following androgen deprivation therapy (from bilateralorchiectomy or treatment with a gonadotrophin-releasing-hormone agonist)for metastatic prostate cancer. Menopause and perimenopause may also beassociated with mood disorders such as depression and anxiety.

Clinicians recognize a distinction among central nervous systemillnesses, and there have been many schemes for categorizing mentaldisorders. The Diagnostic and Statistical Manual of Mental Disorders,Fourth Ed., Text Revision, (hereinafter, the “DSM-IV-TR™”), published bythe American Psychiatric Association, and incorporated herein byreference, provides a standard diagnostic system upon which persons ofskill rely. According to the framework of the DSM-IV-TR™, the CNSdisorders of Axis I include: disorders diagnosed in childhood (such as,for example, attention deficit disorder or “ADD” and attentiondeficit/hyperactivity disorder or “ADHD”) and disorders diagnosed inadulthood. CNS disorders diagnosed in adulthood include (1)schizophrenia and psychotic disorders; (2) cognitive disorders; (3) mooddisorders; (4) anxiety related disorders; (5) eating disorders; (6)substance related disorders; (7) personality disorders; and (8)“disorders not yet included” in the scheme.

Mood disorders are a group of heterogeneous, typically recurrentillnesses including unipolar (depressive) and bipolar (manic-depressive)disorders that are characterized by pervasive mood disturbances,psychomotor dysfunction, and vegetative symptoms.

In its full syndromal expression, clinical depression manifests as majordepressive disorder, with episodic course and varying degrees ofresidual manifestations between episodes. The mood is typicallydepressed, irritable, and/or anxious. The patient may appear miserable,with furrowed brows, downturned corners of the mouth, slumped posture,poor eye contact, and monosyllabic (or absent) speech. The morbid moodmay be accompanied by preoccupation with guilt, self-denigrating ideas,decreased ability to concentrate, indecisiveness, diminished interest inusual activities, social withdrawal, helplessness, hopelessness, andrecurrent thoughts of death and suicide. Sleep disorders are common. Insome, the morbid mood is so deep that tears dry up; the patientcomplains of an inability to experience usual emotions—including grief,joy, and pleasure—and of a feeling that the world has become colorless,lifeless, and dead.

Melancholia (formerly endogenous depression) is characterized by markedpsychomotor slowing (of thinking and activity) or agitation (eg,restlessness, wringing of the hands, pressure of speech), weight loss,irrational guilt, and loss of the capacity to experience pleasure. Moodand activity vary diurnally, with a nadir in the morning. Mostmelancholic patients complain of difficulty falling asleep, multiplearousals, and insomnia in the middle of the night or early morning.Sexual desire is often diminished or lost. Amenorrhea can occur.Anorexia and weight loss may lead to emaciation and secondarydisturbances in electrolyte balance.

In atypical depression, reverse vegetative features dominate theclinical presentation; they include anxious-phobic symptoms, eveningworsening, initial insomnia, hypersomnia that often extends into theday, and hyperphagia with weight gain. Unlike patients with melancholia,those with atypical depression show mood brightening to potentiallypositive events but often crash into a paralyzing depression with theslightest adversity. Atypical depressive and bipolar II disordersoverlap considerably.

In dysthymic disorder, depressive symptoms typically begin insidiouslyin childhood or adolescence and pursue an intermittent or low-gradecourse over many years or decades; major depressive episodes maycomplicate it (double depression). In pure dysthymia, depressivemanifestations occur at a subthreshold level and overlap considerablywith those of a depressive temperament: habitually gloomy, pessimistic,humorless, or incapable of fun; passive and lethargic; introverted;skeptical, hypercritical, or complaining; self-critical,self-reproaching, and self-derogatory; and preoccupied with inadequacy,failure, and negative events.

Thorough evaluation of many persons with depression reveals bipolartraits, and as many as one in five patients with a depressive disorderalso develops frank hypomania or mania. Most switches from unipolar tobipolar disorder occur within 5 years of the onset of depressivemanifestations. Predictors of a switch include early onset of depression(<25 years old), postpartum depression, frequent episodes of depression,quick brightening of mood with somatic treatments (eg, antidepressants,phototherapy, sleep deprivation, electroconvulsive therapy), and afamily history of mood disorders for three consecutive generations.

Between episodes, patients with bipolar disorder exhibit depressivemoodiness and sometimes high-energy activity; disruption indevelopmental and social functioning is more common than in unipolardisorder. In bipolar disorder, episodes are shorter (3 to 6 months), ageof onset is younger, onset of episodes is more abrupt, and cycles (timefrom onset of one episode to that of the next) are shorter than inunipolar disorder. Cyclicity is particularly accentuated inrapid-cycling forms of bipolar disorder (usually defined as >=4episodes/year).

In bipolar I disorder, full-fledged manic and major depressive episodesalternate. Bipolar I disorder commonly begins with depression and ischaracterized by at least one manic or excited period during its course.The depressive phase can be an immediate prelude or aftermath of mania,or depression and mania can be separated by months or years.

In bipolar II disorder, depressive episodes alternate with hypomanias(relatively mild, nonpsychotic periods of usually <1 week). During thehypomanic period, mood brightens, the need for sleep decreases, andpsychomotor activity accelerates beyond the patient's usual level.Often, the switch is induced by circadian factors (eg, going to beddepressed and waking early in the morning in a hypomanic state).Hypersomnia and overeating are characteristic and may recur seasonally(eg, in autumn or winter); insomnia and poor appetite occur during thedepressive phase. For some persons, hypomanic periods are adaptivebecause they are associated with high energy, confidence, andsupernormal social functioning. Many patients who experience pleasantelevation of mood, usually at the end of a depression, do not report itunless specifically questioned.

Patients with major depressive episodes and a family history of bipolardisorders (unofficially called bipolar III) often exhibit subtlehypomanic tendencies; their temperament is termed hyperthymic (ie,driven, ambitious, and achievement-oriented).

In cyclothymic disorder, less severe hypomanic and mini-depressiveperiods follow an irregular course, with each period lasting a few days.Cyclothymic disorder is commonly a precursor of bipolar II disorder. Butit can also occur as extreme moodiness without being complicated bymajor mood disorders. In such cases, brief cycles of retarded depressionaccompanied by low self-confidence and increased sleep alternate withelation or increased enthusiasm and shortened sleep. In another form,low-grade depressive features predominate; the bipolar tendency is shownprimarily by how easily elation or irritability is induced byantidepressants. In chronic hypomania, a form rarely seen clinically,elated periods predominate, with habitual reduction of sleep to <6hours. Persons with this form are constantly overcheerful, self-assured,overenergetic, full of plans, improvident, overinvolved, and meddlesome;they rush off with restless impulses and accost people.

Anxiety disorders are more common than any other class of psychiatricdisorder. Panic attacks are common, affecting >⅓ of the population in asingle year. Most persons recover without treatment; a few develop panicdisorder. Panic disorder is uncommon, affecting <1% of the population ina 6-month period. Panic disorder usually begins in late adolescence orearly adulthood and affects women two to three times more often thanmen. Phobic disorders involve persistent, unrealistic, yet intenseanxiety that, unlike the free-floating anxiety of panic disorder, isattached to external situations or stimuli. Persons who have a phobiaavoid such situations or stimuli or endure them only with greatdistress. However, they retain insight and recognize the excessivenessof their anxiety. In agoraphobia, anxiety about or avoidance of beingtrapped in situations or places with no way to escape easily if panicdevelops. Agoraphobia is more common than panic disorder. It affects3.8% of women and 1.8% of men during any 6-month period. Peak age ofonset is the early 20s; first appearance after age 40 is unusual. Inspecific phobias, clinically significant anxiety is induced by exposureto a specific situation or object, often resulting in avoidance.Specific phobias are the most common anxiety disorders but are oftenless troubling than other anxiety disorders. They affect 7% of women and4.3% of men during any 6-month period.

One form of anxiety disorder is social phobia, which is a clinicallysignificant anxiety induced by exposure to certain social or performancesituations, often resulting in avoidance. Social phobias affect 1.7% ofwomen and 1.3% of men during any 6-month period. However, more recentepidemiologic studies suggest a substantially higher lifetime prevalenceof about 13%. Men are more likely than women to have the most severeform of social anxiety, avoidant personality disorder.

Yet another anxiety disorder is Obsessive-Compulsive Disorder (OCD), adisorder characterized by recurrent, unwanted, intrusive ideas, images,or impulses that seem silly, weird, nasty, or horrible (obsessions) andby urges to do something that will lessen the discomfort due to theobsessions (compulsions). Obsessive-compulsive disorder occurs aboutequally in men and women and affects 1.6% of the population during any6-month period.

Posttraumatic Stress Disorder is another anxiety disorder. It is adisorder in which an overwhelming traumatic event is reexperienced,causing intense fear, helplessness, horror, and avoidance of stimuliassociated with the trauma. The stressful event involves serious injuryor threatened death to the person or others or actual death of others;during the event, the person experiences intense fear, helplessness, orhorror. Lifetime prevalence is at least 1%, and in high-riskpopulations, such as combat veterans or victims of criminal violence,prevalence is reported to be between 3% and 58%.

Acute stress disorder resembles posttraumatic stress disorder in thatthe person has been traumatized, reexperiences the trauma, avoidsstimuli that remind him of the trauma, and has increased arousal.However, by definition, acute stress disorder begins within 4 weeks ofthe traumatic event and lasts a minimum of 2 days but no more than 4weeks. A person with this disorder has three or more of the followingdissociative symptoms: a sense of numbing, detachment, or absence ofemotional responsiveness; reduced awareness of surroundings (eg, beingdazed); a feeling that things are not real; a feeling that he is notreal; and amnesia for an important part of the trauma. The prevalence ofacute stress disorder is unknown but is presumably proportionate to theseverity of the trauma and the extent of exposure to the trauma.

Generalized Anxiety Disorder is an excessive, almost daily, anxiety andworry for ≧6 months about a number of activities or events. Generalizedanxiety disorder is common, affecting 3 to 5% of the population within a1-year period. Women are twice as likely to be affected as men. Thedisorder often begins in childhood or adolescence but may begin at anyage.

Anxiety may be secondary to physical disorders, such as neurologicdisorders (eg, brain trauma, infections, inner ear disorders),cardiovascular disorders (eg, heart failure, arrhythmias), endocrinedisorders (eg, overactive adrenal or thyroid glands), and respiratorydisorders (eg, asthma, chronic obstructive pulmonary disease). Anxietymay be caused by use of drugs, such as alcohol, stimulants, caffeine,cocaine, and many prescription drugs. Also, drug withdrawal is commonlyassociated with anxiety.

An estimated 4 to 5 million Americans (about 2% of all ages and 15% ofthose >age 65) have some form and degree of cognitive failure (cognitivedisorder). Cognitive failure (dysfunction or loss of cognitivefunctions—the processes by which knowledge is acquired, retained, andused) is most commonly due to delirium (sometimes called acuteconfusional state) or dementia. It may also occur in association withdisorders of affect, such as depression.

Delirium (Acute Confusional State) is a clinical state characterized byfluctuating disturbances in cognition, mood, attention, arousal, andself-awareness, which arises acutely, either without prior intellectualimpairment or superimposed on chronic intellectual impairment. Somepractitioners use the terms delirium and acute confusional statesynonymously; others use delirium to refer to a subset of confusedpeople with hyperactivity. Still others use delirium to refer tofull-blown confusion and confusional state to refer to milddisorientation.

Dementia is a chronic deterioration of intellectual function and othercognitive skills severe enough to interfere with the ability to performactivities of daily living. Dementia may occur at any age and can affectyoung people as the result of injury or hypoxia. However, it is mostly adisease of the elderly, affecting >15% of persons >65 years old and asmany as 40% of persons >80 years old. It accounts for more than half ofnursing home admissions and is the condition most feared by agingadults.

Alzheimer's Disease is a progressive, inexorable loss of cognitivefunction associated with an excessive number of senile plaques in thecerebral cortex and subcortical gray matter, which also containsβ-amyloid and neurofibrillary tangles consisting of tau protein.

Lewy body dementia may be the second most common dementia afterAlzheimer's disease. Lewy bodies are hallmark lesions of degeneratingneurons in Parkinson's disease and occur in dementia with or withoutfeatures of Parkinson's disease. In Lewy body dementia, Lewy bodies maypredominate markedly or be intermixed with classic pathologic changes ofAlzheimer's disease. Symptoms, signs, and course of Lewy body dementiaresemble those of Alzheimer's disease, except hallucinations (mainlyvisual) are more common and patients appear to have an exquisitesensitivity to antipsychotic-induced extrapyramidal adverse effects.

Cerebrovascular disease can destroy enough brain tissue to impairfunction. Vascular dementia, which includes impairment due to single,strategically located infarcts or to multiple small infarcts from smallor medium-sized vessel disease, is more common in men and generallybegins after age 70. It occurs more often in persons who havehypertension and/or diabetes mellitus or who abuse tobacco. Progressivevascular dementia can generally be slowed by controlling blood pressure,regulating blood sugar (90 to 150 mg/dL), and stopping smoking. Somedegree of vascular damage is found in up to 20% of autopsies of patientswith dementia.

Binswanger's dementia (subcortical arteriosclerotic encephalopathy) isuncommon and involves multiple infarcts in deep hemispheric white matterassociated with severe hypertension and systemic vascular disease.Although clinically similar to vascular dementia, Binswanger's dementiamay be characterized by more focal neurologic symptoms associated withacute strokes and a more rapid course of deterioration. MRI and CT showareas of leukoencephalopathy in the cerebrum semiovale adjacent to thecortex.

More than 25% of patients with Parkinson's disease have dementia; someestimates are as high as 80% (see Ch. 179). At autopsy, patients withParkinson's disease may have some of the neuropathologic brain findingsand many of the biochemical changes seen in patients with Alzheimer'sdisease. A less severe subcortical dementia is also associated withParkinson's disease.

The dementia associated with progressive supranuclear palsy is commonlypreceded by other neurologic symptoms, eg, multiple falls, dystonicaxial rigidity, retrocollis, supranuclear opthalmoplegia, dysphagia, anddysarthria.

Patients with Huntington's disease (chorea) may also present withsymptoms of dementia, but the diagnosis is usually clarified by thefamily history, younger age at onset, and the disease's characteristicmotor abnormalities. In case of doubt, genetic analysis can bediagnostic.

Pick's disease is a less common form of dementia, affecting the frontaland temporal regions of the cortex. Patients have prominent apathy andmemory disturbances; they may show increased carelessness, poor personalhygiene, and decreased attention span. Although the clinicalpresentation and CT findings in Pick's disease can be quite distinctive,definitive diagnosis is possible only at autopsy. The Klüver-Bucysyndrome can occur early in the course of Pick's disease, with emotionalblunting, hypersexual activity, hyperorality (bulimia and sucking andsmacking of lips), and visual agnosias.

Frontal lobe dementia syndromes may result from intrinsic pathology, aprimary or metastatic tumor, previous surgical manipulation, irradiationto the brain, or severe head trauma. The repeated head trauma indementia pugilistica, which occurs in professional fighters, appears tolink genetically to the 4 allele of apo E.

Normal-pressure hydrocephalus is characterized by a triad of progressivedementia, incontinence, and an unsteady, slow, and wide-based gait.Onset is usually insidious and occurs mostly in late middle or old age.The disease is more common in men and occasionally is related to priormeningitis, subarachnoid hemorrhage, head injury, or neurosurgicalinterventions. In most cases, evidence of precedent injury is lacking.Normal-pressure hydrocephalus may result from scarring of arachnoidvilli over convexities of the brain, which results in slowed absorptionof CSF (ceresbrospinal fluid), ventricular dilatation, and frontal lobemotor abnormalities. The laboratory diagnosis is based on high-normalCSF pressure (150 to 200 mm Hg) and CT evidence of ventriculardilatation and narrowed cerebral sulci at the brain's apex withoutwidening of the subarachnoid space. The results of treatment with CSFshunting are inconsistent. The dementia is sometimes reversible; someexperts recommend a therapeutic lumbar puncture to remove about 30 mL ofCSF. Improvement in gait and cognition for hours or several dayssuggests the value of shunt placement.

Subdural hematoma can cause a change in mental status, producing coma,delirium, or a dementia syndrome. Cognitive changes may begin any timeafter blood begins to accumulate and can progress rapidly or slowly,according to the size and location of the hematoma. This chronicsyndrome may resemble vascular dementia, with focal neurologic signs andcognitive changes. Removing the hematoma may restore function or preventfurther loss of intellectual function. However, some experts believethat after hematomas have exerted pressure on the brain for a long time(perhaps a year or more), removing them does little to improve cognitivefunction.

The most well-known infectious cause of dementia is Creutzfeldt-Jakobdisease, in which memory deficits, electroencephalographic changes,myoclonus, and sometimes ataxia are prominent. The infectious agent is acorrupted protein called a prion that can be acquired genetically, bytissue transplantation, by cannibalism, and apparently by eatingproducts from infected cattle (with mad-cow disease). Most cases occursporadically. It produces a characteristic spongiform encephalopathyquite different from the changes of Alzheimer's disease. The course ismore rapid than that of Alzheimer's disease and usually lasts from 6 to12 months.

Patients with Gerstmann-Sträussler-Scheinker disease, another dementiawith a prion-related cause, typically present with ataxia, followedlater by cognitive decline. This syndrome affects younger persons andhas a longer duration than Creutzfeldt-Jakob disease.

General paresis, a form of neurosyphilis, was once a common cause ofdementia in Western societies. It is still prevalent in developingcountries. In addition to intellectual decline, tremors and pupillarychanges can occur. The CSF is tested using the fluorescent treponemalantibody (FTA) test. A positive FTA test for syphilis establishes thediagnosis.

AIDS dementia can complicate the later stages of HIV infection. Dementiamay be caused by HIV, by the JC virus that causes progressive multifocalleukoencephalopathy, or by a variety of other opportunistic infectiousagents, including fungi, bacteria, viruses, or protozoa that can beidentified at autopsy. Early manifestations include slowed thinking andexpression, difficulty in concentration, and apathy, with preservedinsight and few manifestations of depression. Motor movements areslowed; ataxia and weakness may be evident. Reflexes, including theextensor plantar responses, become abnormal. Treatment with zidovudineoften induces improvement sometimes verging on the dramatic.

Therefore, there exists a need to develop effective and minimallyadverse therapies for the above listed disorders.

SUMMARY OF THE INVENTION

The present invention generally relates to pharmaceutical compositionscomprising eszopiclone or a pharmaceutically acceptable salt, solvate,clathrate, polymorph, or co-crystal thereof, and trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine ortrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine. Thepharmaceutical compositions of the invention are useful in the treatmentof menopause, perimenopause, mood disorders, anxiety disorders, andcognitive disorders.

In addition, the present invention relates to a method for augmentationof antidepressant therapy in a patient comprising administering to thepatient a therapeutically effective amount of eszopiclone, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof. The present invention also relates to a method foreliciting a dose-sparing effect in a patient undergoing treatment withtrans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine ortrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenaminecomprising administering to the patient a therapeutically effectiveamount of eszopiclone, or a pharmaceutically acceptable salt, solvate,clathrate, polymorph, or co-crystal thereof.

Furthermore, the present invention relates to a method for reducingdepression relapse in a patient who received trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine ortrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenaminetreatment comprising administering to the patient a therapeuticallyeffective amount eszopiclone, or a pharmaceutically acceptable salt,solvate, clathrate, polymorph, or co-crystal thereof.

Co-administration of eszopiclone, a sedative agent, together with antrans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine ortrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine isbeneficial in treatment of such disorders as menopause, perimenopause,mood disorders, anxiety disorders, and cognitive disorders.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates generally to pharmaceutical compositionscontaining two or more active agents that when taken together havebenefit in treatment of menopause, perimenopause, mood disorder, anxietydisorder, or cognitive disorder. In certain embodiments, the presentinvention relates to a pharmaceutical composition comprising eszopicloneand trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine ortrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine. In oneembodiment, eszopiclone of the above listed embodiments is present as apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof. In another embodiment, trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine ortrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine ispresent as a pharmaceutically acceptable salt, solvate, clathrate,polymorph, or co-crystal thereof.

Another aspect of the present invention relates to a method of treatinga patient suffering from menopause, perimenopause, mood disorder,anxiety disorder, or cognitive disorder comprising the step ofadministering to said patient a therapeutically effective dose of apharmaceutical composition containing two or more active agents thatwhen taken together improve the quality of sleep or sleep disorders forsaid patient.

Further aspect of the present invention relates to a method of treatinga patient suffering from menopause, perimenopause, mood disorder,anxiety disorder, or cognitive disorder comprising the step ofadministering to said patient a therapeutically effective dose of apharmaceutical composition containing two or more active agents thatwhen taken together improve the treatment of the patient.

In another embodiment, the present invention relates to a method foraugmentation of trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine ortrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine therapyin a patient comprising administering to the patient a therapeuticallyeffective amount of eszopiclone, or a pharmaceutically acceptable salt,solvate, clathrate, polymorph, or co-crystal thereof.

The present invention also relates to a method for eliciting adose-sparing effect in a patient undergoing treatment with trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine ortrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenaminecomprising administering to the patient a therapeutically effectiveamount of eszopiclone, or a pharmaceutically acceptable salt, solvate,clathrate, polymorph, or co-crystal thereof.

Furthermore, the present invention relates to a method for reducingdepression relapse in a patient who received trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine ortrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenaminetreatment comprising administering to the patient a therapeuticallyeffective amount of eszopiclone, or a pharmaceutically acceptable salt,solvate, clathrate, polymorph, or co-crystal thereof.

Eszopiclone

Eszopiclone is a cyclopyrrolone that has the chemical name (+)6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3-4-b]pyrazineor (+)6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl4-methylpiperazine-1-carboxylate. The chemical structure of eszopicloneis shown below:

Eszopiclone is the S-(+)-optical isomer of the compound zopiclone, whichis described in U.S. Pat. Nos. 6,319,926 and 6,444,673. Racemiczopiclone is described in Goa and Heel, [Drugs, 32:48-65 (1986)] and inU.S. Pat. Nos. 3,862,149 and 4,220,646. S-(+)-zopiclone, which willhereinafter be referred to by its USAN-approved generic name,eszopiclone, includes the optically pure and the substantially opticallypure (e.g., 90%, 95% or 99% optical purity) S-(+)-zopiclone isomer.

Zopiclone was the first of a chemically distinct class of hypnotic andanxiolytic compounds that offers a psychotherapeutic profile of efficacyand side effects similar to the benzodiazepines. Some members of thisclass of compounds, the cyclopyrrolones, appear to cause less residualsedation and less slowing of reaction times than the benzodiazepines,and it offers the promise of an improved therapeutic index overbenzodiazepines. Recently, the USFDA approved use of eszopiclone(LUNESTA™) for the treatment of insomnia.

Eszopiclone possesses potent activity in treating sleep disorders suchas insomnia. Eszopiclone also possess potent activity in treating sleepdisorders while avoiding the usual adverse effects including but notlimited to drowsiness, next day effects tiredness in the morning,inability to concentrate and headache. U.S. Pat. No. 5,786,357 relatesto methods of using eszopiclone also to treat convulsive disorders suchas epilepsy.

The size of a prophylactic or therapeutic dose of eszopiclone in theacute or chronic management of disease will vary with the severity ofthe condition to be treated and the route of administration. The dose,and perhaps the dose frequency, will also vary according to the age,body weight, and response of the individual patient. In general, thetotal daily dose ranges, for the conditions described herein, is fromabout 0.25 mg to about 10 mg. Preferably, a daily dose range should bebetween about 0.5 mg to about 5 mg. Most preferably, a daily dose rangeshould be between about 0.5 mg to about 3.0 mg. In one embodiment, thedaily dose is 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, or 3.0 mg. Inmanaging the patient, the therapy may be initiated at a lower dose,perhaps about 0.5 mg to about 2 mg and increased depending-on thepatient's global response. It is further recommended that children andpatients over 65 years, and those with impaired renal or hepaticfunction, initially receive low doses, and that they be titrated basedon global response and blood level. It may be necessary to use dosagesoutside these ranges in some cases.

In the case where an oral composition is employed, a suitable dosagerange for use is from about 0.25 mg to about 10.0 mg with, in the usualcase, the lower doses serving more common insomnia, and the higherdoses, presented in divided dosing, reserved for control of psychiatricdisorders. Preferably, a dose range of between about 0.5 mg to about 5mg is given as a once daily administration or in divided doses ifrequired; most preferably, a dose range of from about 0.5 mg to about 3mg is given, either as a once daily administration or in divided dosesif required. Patients may be upward titrated from below to within thisdose range to a satisfactory control of symptoms as appropriate.

trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine

Sertraline, whose chemical name is (1S,4S)-cis4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, isapproved for the treatment of depression by the United States Food andDrug Administration, and is available under the trade name ZOLOFT®(Pfizer Inc., NY, N.Y., USA). The use of sertraline, (1R,4S)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine and(1S,4R)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine forthe treatment of psychoses, psoriasis, rheumatoid arthritis andinflammation are disclosed in U.S. Pat. No. 4,981,870. The receptorpharmacology of the individual (1S,4R) and (1R,4S) enantiomers of trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, isdescribed by Welch et al., J. Med. Chem., 27:1508-1515 (1984).

The present invention utilizes (1R,4S)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine (A);and (1S,4R)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine (B):

Compounds A or B are useful in treatment of menopause, perimenopause,and mood, anxiety, and cognitive disorders. The magnitude of aprophylactic or therapeutic dose of A or B will vary with the nature andseverity of the condition to be treated and the route of administration.The dose, and perhaps the dose frequency, will also vary according tothe age, body weight and response of the individual patient. In general,the total daily dose ranges of A and B are from about 25 mg per day toabout 1000 mg per day, preferably about 100 mg per day to about 600 mgper day, in single or divided doses.

Preparation of the compounds A and B is illustrated below in Scheme 1and its accompanying narrative.

In the compound

of Scheme 1, R is

wherein R¹, R² and R³ are each independently alkyl. In a preferredembodiment of the

compounds, R is t-butyl.

Synthesis of 2-methyl-propane-2-sulfinic acid [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-y-yl]-amide (Tetralonet-butanesulfinimine): To a solution of4-((3,4-dicholorophenyl)-3,4-dihydro-1-naphthalenone (12 g) in THF (40mL) was added (R)-t-butanesulfinamide (5.2 g) and Ti(OEt)₄ (85 mL 20%)in EtOH. The reaction mixture was heated to 60° C. for 13 h. Thereaction mixture was cooled to rt, and poured to a brine solution (100mL) with stirring. The suspension was then added EtOAc (300 mL) andstirred to 10 min. The suspension was filtered and the filtrate wasconcentrated to ca 50 mL. It was then added EtOAc (100 mL), the organicphase was then separated and concentrated to give a crude reactionmixture. The final products were isolated from the crude products bycareful flash column using EtOAc and hexane (3:7 to 1:1) to give ca 3 gstarting ketone, and(1R,4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenonetert-butanesulfinimine (2.5 g, first product) as an oil that solidifiedon standing. ¹H NMR (CDCl₃) δ 1.33 (S, 9H), 2.10-2.20 (m, 1H), 2.28-2.38(m, 1H) 2.88-2.98 (m, 1H), 3.34-3.44 (m 1H), 4.12-4.24 (m, 1H),6.84-6.88 (m, 2H), 7.20 (s, 1H), 7.25-7.40 (m, 3H), 8.22-8.28 (m, 1H).

The other product (1R,4R)-4-(3,4-dichlorophenyl)-3-4-dihydro-1-naphthalenone t-butanesulfinimine (3.0 g, secondproduct, lower R_(f)) was isolated also as oil that solidified onstanding. ¹H NMR (CDCl₃) δ 1.34 (S, 9H), 2.05-2.18 (m, 1H), 2.28-2.38(m, 1H), 3.15-3.25 (m, 2H), 4.16-4.22 (m, 1H), 6.84-6.88 (m, 2H), 7.20(s, 1H), 7.25-7.40 (m, 3H), 8.22-8.28 (m, 1H).

Synthesis of (R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone:(1R,4R)-4-(3,4-dichlorophenyl)3,4-dihydro-1-naphthalenonet-butanesulfinimine (3.0 g, second product) was dissolved in MeOH (20mL) and concentrated HCl (4 mL) at rt. The reaction mixture was stirredat rt to give a suspension. It was filtered and the solids were washedwith hexane to give 1.2 g product. The enantiomeric purity wasdetermined to be >99.3% by HPLC analysis with a ChiralPak AS 10 μm,4.6×250 mm, Hexane/IPA (90:10), UV 220 nm, R-isomer 8.23 min. S-isomer12.25 min. ¹H NMR (CDCl₃) δ 2.20-2.32 (m, 1H), 2.42-2.53 (m, 1H)2.57-2.78 (m, 2H), 4.28 (dd=4.6, 8.1 Hz, 1H), 6.95 (dd, J=2.1, 7.6 Hz,2H), 7.23 (d J=2.0 Hz, 1H), 7.37-50 (m, 3H), 8.13 (d, J=7.6 Hz, 1H).[α]=−66° (c=1, acetone).

Synthesis of (S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone Theprevious procedure was used, starting from(1R,4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenonet-butanesulfinimine. 1.7 g of product (>99% ee) was obtained. [α]=+62,c=1, acetone). ¹H NMR spectrum of the product is the same as that of itsenantiomer.

Synthesis of (1S,4R) and(1R,4R)—N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-formamide:(R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone (1.2 g) was addedformic acid (3 mL) and formamide (3 mL). The reaction mixture was heatedto 160-165° C. for 15 h under nitrogen atmosphere. The reaction mixturewas cooled to rt and decanted the solvent. The residue solids was passedthrough flash column using EtOAc:Hexane (3:7 to 1:1) to give and(1R,4R)-Norsertralaine formamide (400 mg, first spot), and(1S,4R)-Norsertraline formamide (360 mg). ¹H NMR of the first product[(1R,4R)-isomer]: (CDCl₃) δ 1.80-2.10 (m, 3H), 2.10-2.20 (m, 1H),4.00-4.10 (m, 1H), 5.22-5.30 (m, 1H), 6.10-6.20 (m, 1H), 6.80-6.90 (M,1H), 6.90-6.96 (m, 1H), 7.10-7.40 (m, 5H), 8.22 (s, 1H). M+320. ¹H NMRof the second product [(1S,4R)-isomer: δ 1.64-1.90 (m, 2H), 2.10-2.28(m, 2H), 4.10 (m, 1H), 5.38-5.42 (m, 1H), 5.82-6.05 (m, 1H), 6.80-6.90(m, 2H), 7.10-40 (m, 5H), 8.28 (s, 1H). Mass Spec. M⁺ 320.

The products were reduced to the corresponding A and B by borane.

Synthesis of (1S*,4R*)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine HCl(racemic mixture of A and B HCl): (1S*,4R*) formamide (1.0 g) wasdissolved in THF (7 mL), and added BH₃ THF (1M, 9.3 mL, 3 eq. Thereaction mixture was heated to 75-80° C. for 3 h and stirred at rtovernight. The reaction mixture was quenched with MeOH (20 mL). Themixture was concentrated to give a residue, which was dissolved in 10%HCl (20 mL). The solution was heated to 80-90° C. for 9 h, and basifiedwith potassium carbonate, and extracted with EtOAc (25 mL). The organicphase was separated and washed with water, brine, dried over Na₂SO₄.Concentrated to give the free base. It was converted to its HCl salt inTBME with HCl/Et₂O to give the product (0.75 g). ¹H MNR (CD₃OD) δ1.86-1.96 (m, 1H), 2.04-2.12 (m, 1H), 2.18-2.28 (m, 1H), 2.30-2.42 (m,1H), 2.78 (s, 3H), 4.34 (m, 1H), 4.60 (m, 1H), 6.93-7.00 (m, 2H), 7.15(s, 1H), 7.34-7.44 (m, 3H), 7.57-7.59 (d, J=7.2 Hz, 1H). Mass Spec. M⁺305.

Synthesis of (1S,4R)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine HClby Resolution with (S)-Mandelic Acid: Racemic trans-sertraline (3 g) wasdissolved in anhydrous ethanol (30 g) and added (S)-mandelic acid (1.5g). The reaction mixture was heated to reflux for 30 min. and cooled tort. The reaction solution was concentrated to give oil (ca 3 mL ethanolleft). To it was added EtOAc (30 mL) and stirred for 1 h at rt. Thesolid formed from the solution was collected by filtration and dried(1.73 g). The solid was dissolved in hot EtOAc (35 mL), and cooled to rtin 30 min, and stirred for 1 h. The solid was collected by filtrationand dried to give (1S,4R)-sertraline-(S)-mandelate (1.3 g). Ee of theproduct was >99% by HPLC. The solid (1.1 g) was converted to its freebase with potassium carbonate, and treated with HCl/ether in MeOH togive the HCl salt (0.73 g). ¹H NMR spectrum was identical to itsracemate. (1R,4S)-sertraline HCl was prepared from the mother liquor,after enriched with (R)-mandelic acid. Mass Spec M⁺ 305.

The commercial form of sertraline [(S,S)-cis] and its isomeric analogueswere tested for their inhibition of functional uptake of serotonin(5-HT), norepinephrine (NE), or dopamine (DA), in synaptosomes preparedfrom rat whole brain, hypothalamus, or corpus striatum, respectively.Compounds were tested initially at 10 μM in duplicate, and if >50%inhibition of uptake was observed, they were tested further at 10different concentrations in duplicate in order to obtain full inhibitioncurves. IC₅₀ values (concentration inhibiting control activity by 50%)was then determined by nonlinear regression analysis of the inhibitioncurves and tabulated below in the Examples sections.

trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine

(1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine(P) and (1S,4R)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine (Q) areuseful in the treatment of menopause, perimenopause, and mood, anxiety,and cognitive disorders. The magnitude of a prophylactic or therapeuticdose of P or Q will vary with the nature and severity of the conditionto be treated and the route of administration. The dose, and perhaps thedose frequency, will also vary according to the age, body weight andresponse of the individual patient. In general, the total daily doseranges of compounds P or Q will be from about 25 mg per day to about1000 mg per day, preferably about 100 mg per day to about 600 mg perday, in single or divided doses.

Compounds P and Q are represented by the formulae:

Preparation of compounds P and Q is illustrated below in Scheme 2 andits accompanying narrative.

In the compound

of Scheme 1,

R is

wherein R¹, R² and R³ are each independently alkyl. In a preferredembodiment of the compounds, R is tert-butyl.

Synthesis of 2-methyl-propane-2-sulfinic acid[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-y-yl]-amide(tetralone t-butanesulfinimine): To a solution of4-((3,4-dicholorophenyl)-3,4-dihydro-1-naphthalenone (12 g) in THF (40mL) was added (R)-t-butanesulfinamide (5.2 g) and Ti(OEt)₄ (85 mL 20%)in EtOH. The reaction mixture was heated to 60° C. for 13 h. Thereaction mixture was cooled to rt, and poured into a brine solution (100mL) with stirring. The suspension was then added to EtOAc (300 mL) andstirred for 10 min. The suspension was filtered and the filtrate wasconcentrated to ca 50 mL. One hundred milliliters of EtOAc was added andthe organic phase was separated and concentrated to give a crudereaction mixture. The final products were isolated from the crudeproducts by careful flash column chromatography using EtOAc and hexane(3:7 to 1:1) to give ca 3 g starting ketone, and(1R,4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenonetert-butanesulfinimine (2.5 g, first product) as an oil that solidifiedon standing. ¹H NMR (CDCl₃) δ 1.33 (S, 9H), 2.10-2.20 (m, 1H), 2.28-2.38(m, 1H) 2.88-2.98 (m, 1H), 3.34-3.44 (m 1H), 4.12-4.24 (m, 1H),6.84-6.88 (m, 2H), 7.20 (s, 1H), 7.25-7.40 (m, 3H), 8.22-8.28 (m, 1H).The other product (1R,4R)-4-(3,4-dichlorophenyl)-3-4-dihydro-1-naphthalenone tert-butanesulfinimine (3.0 g,second product, lower R_(f)) was isolated also as an oil that solidifiedon standing. ¹H NMR (CDCl₃) δ 1.34 (S, 9H), 2.05-2.18 (m, 1H), 2.28-2.38(m, 1H), 3.15-3.25 (m, 2H), 4.16-4.22 (m, 1H), 6.84-6.88 (m, 2H), 7.20(s, 1H), 7.25-7.40 (m, 3H), 8.22-8.28 (m, 1H).

Synthesis of (R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone:(1R,4R)-4-(3,4-dichlorophenyl)3,4-dihydro-1-naphthalenonet-butanesulfinimine (3.0 g, second product) was dissolved in MeOH (20mL) and concentrated HCl (4 mL) at rt. The reaction mixture was stirredat rt to give a suspension. It was filtered and the solids were washedwith hexane to give 1.2 g product. The enantiomeric purity wasdetermined to be >99.3% by HPLC analysis with a ChiralPak AS10 μm,4.6×250 mm, Hexane/IPA (90:10), UV 220 nm, R-isomer 8.23 min. S-isomer12.25 min. ¹H NMR (CDCl₃) δ 2.20-2.32 (m, 1H), 2.42-2.53 (m, 1H)2.57-2.78 (m, 2H), 4.28 (dd=4.6, 8.1 Hz, 1H), 6.95 (dd, J=2.1, 7.6 Hz,2H), 7.23 (d J=2.0 Hz, 1H), 7.37-50 (m, 3H), 8.13 (d, J=7.6 Hz, 1H).[α]=−66° (c=1, acetone).

Synthesis of (S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone Theprevious procedure was used, starting from(1R,4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenonetert-butanesulfinimine. 1.7 g of product (>99% ee) was obtained. [α]=+62(c=1, acetone). ¹H NMR spectrum of the product is the same as that ofits enantiomer.

Synthesis of (1S,4R) and(1R,4R)—N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-formamide:(R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone (1.2 g) was addedformic acid (3 mL) and formamide (3 mL). The reaction mixture was heatedto 160-165° C. for 15 h under nitrogen atmosphere. The reaction mixturewas cooled to rt and decanted the solvent. The residue solids was passedthrough flash column using EtOAc:Hexane (3:7 to 1:1) to give the(1R,4R)-formamide (400 mg, first spot), and the (1S,4R)-formamide (360mg). ¹H NMR of the first product [(1R,4R)-isomer]: (CDCl₃) δ 1.80-2.10(m, 3H), 2.10-2.20 (m, 1H), 4.00-4.10 (m, 1H), 5.22-5.30 (m, 1H),6.10-6.20 (m, 1H), 6.80-6.90 (M, 1H), 6.90-6.96 (m, 1H), 7.10-7.40 (m,5H), 8.22 (s, 1H). M+320. ¹H NMR of the second product [(1S,4R)-isomer:δ 1.64-1.90 (m, 2H), 2.10-2.28 (m, 2H), 4.10 (m, 1H), 5.38-5.42 (m, 1H),5.82-6.05 (m, 1H), 6.80-6.90 (m, 2H), 7.10-40 (m, 5H), 8.28 (s, 1H).Mass Spec. M⁺ 320.

Synthesis of (1S,4R)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: (1S,4R)formamide (ca 300 mg) was dissolved in MeOH (5 mL) followed by additionof 6N HCl (6 mL). The reaction mixture was heated to 80° C. for 2 h. Thereaction mixture was cooled to rt for 1 h and filtered to collect thesolid. It was washed with acetone (3 mL) and dried to give the product(280 mg). Enantiomeric purity was determined to be >99.8% by HPLCanalysis with a ChiralPak AD 10 μm, 4.6×250 mm,

Hexane/IPA/DEA (99:1:0.1), LUV 220 nm, (1R,4S)-isomer, 11.00 min.(1S,4R)-isomer 11.70 min [α]=−51° (C=1, MeOH). ¹H NMR (CD₃OD) δ1.86-1.97 (m, 2H), 2.20-2.42 (m, 2H), 4.30 (broad s, 1H), 4.67 (broad s,1H), 4.87 (s, 3H), 6.95-6.99 (m, 2H), 7.18 (s, 1H), 7.28-7.50 (m, m,4H). M⁺ 293.

Synthesis of (1R,4S)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: It wasobtained similarly from (1R,4S) formamide with HCl hydrolysis. Ee of theproduct is >99.8% based on HPLC analysis with a ChiralPak AD 10 μm,4.6×250 mm, Hexane/IPA/DEA (99:1:0.1), UV 220 nm, (1R,4S)-isomer 11.00min. (1S,4R)-isomer 11.70 min.

Synthesis of (1R,4R)-cis4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: It wasobtained similarly from (1R,4R) formamide with HCl hydrolysis.Enantiomeric purity was determined to be 96.8% by HPLC analysis with aChiralPak AD 10 μm, 4.6×250 mm, Hexane/IPA/DES (99:1:0.1), UV 220 nm,(1R,4R)-isomer 11.84 min. (1S,4S)-isomer 9.80 min. ¹H NMR (CD₃OD) δ1.96-2.26 (m, 4H), 4.14-4.22 (m, 1H), 4.54-4.63 (m, 1H), 4.87 (s, 3H),7.88-7.94 (m, 1H), 7.18-7.20 (m, 1H), 7.30-7.50 (m, 5H). Mass Spec M⁺292.

Synthesis of (1S,4S)-cis4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: It wasobtained similarly from (1S,4S) formamide. Ee of the product was 98.5%by HPLC analysis. ¹H NMR spectrum is the same as the enantiomer. MassSpec M⁺ 292.

Alternatively, compound P may be prepared as illustrated below in Scheme3 and its accompanying narrative.

Charge 4-(S)-(3,4-dichloro-phenyl)-3,4-dihydro-2H-naphthalen-1-one (1kg, 3.4 mol) and (R)-tert-butylsulphinamide (TBSA, 464 g, 3.8 mol) to asuitable reactor and dissolved in about 7 L THF. Add a 20% wt solutionof Titanium ethoxide in ethanol (about 7.8 kg, 6.9 mol) and heat themixture to about 70° C. for about 24h. The reaction is monitored byHPLC, and after the reaction is complete, cool the mixture to roomtemperature and added a 24% wt aqueous solution of NaCl to the mixture.The resultant slurry was filtered and washed multiple times with about 1L total of ethyl acetate. The mother liquors and washes wereconcentrated to a minimum volume. The aqueous phase was extracted withabout 5 L of ethyl acetate and evaporated to dryness.

The contents were then dissolved in about 7 L of THF and cooled to about−10° C. About 9 kg, (˜5 mol) of a 0.5 M solution of 9-borabicyclononane(9-BBN) in THF, was added slowly (about 3 h) and the mixture was stirredat 0° C. until reaction completion. A 6N HCl/methanol (˜2 L) was addedto the mixture and stirred until the hydrolysis reaction was complete.After neutralization with about 2 L of 6N aqueous NaOH, the mixture wasdistilled to remove THF and the residue (aqueous phase) was extractedtwice with methyl t-butyl ether (2×6 L). The organic phase was thenwashed with water. The organic phase was concentrated, then cooled to 0°C. followed by addition of 2N HCl in methyl t-butyl ether (3 L). Theproduct slowly precipitated as the HCl salt during the addition. Theslurry was filtered and washed with methyl t-butyl ether (2×2 L). Theproduct was dried under vacuum at about 45° C. to afford about 850 g ofRe-Crystallization of crude(1R,4S)-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamineHCl.

The resulting(1R,4S)-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamineHCl (850 g) was charged to a suitable reactor and about 30 L ofdenatured ethanol was added. The mixture was heated to reflux, thevolume was reduced to about 50% via distillation, and then cooled to 50°C. About 30 L of Hexane was added to the slurry to complete the productcrystallization and then the slurry was cooled to about 0° C. Theproduct was isolated by filtration, the cake was washed with about 2 Lof ethanol/hexane (1/3 v/v) and then about 2 L of ethyl acetate,followed by about 3 L of hexane. The wet cake was dried under vacuum atabout 45° C. to afford 630 g of product.

Another alternative process for preparation of compound P is presentedbelow.

4-(S)-(3,4-dichloro-phenyl)-3,4-dichloro-2H-naphthalen-1-one (4.11 kg)and (R)-tert-butylsulphinamide (TBSA, 1.9 kg) were charged to a suitablereactor and dissolved in 29 L THF. A 20% wt solution of titaniumethoxide in ethanol (31.6 kg) was added and the mixture was heated to70° C. with stirring. The reaction is monitored by HPLC, and after thereaction was complete (20-24 h) the mixture was cooled to roomtemperature and added to 20 L of a 24 wt % aqueous solution of NaCl. Theresultant slurry was filtered and washed 3 times with ethyl acetate (4.1L). The mother liquors and washes were concentrated to a minimum volume.The aqueous phase was extracted with about 20 L of a 1:1 mix of ethylacetate and toluene. The organic phases were combined and concentratedto half volume to give a solution of 2. A purified sample of 2 wasanalyzed: m.p. 104° C., ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.23 (dd, 1H,J=7.9, 0.9 Hz), 7.38 (ddd, 1H, J=14.7, 7.3, 1.5 Hz), 7.37 (d, 1H, J=8.4Hz), 7.33 (d, 1H, J=7.7 Hz), 7.17 (d, 1H, J=1.8 Hz), 6.93 (d, 1H, J=7.7Hz), 6.89 (dd, 1H, J=8.4, 2.2 Hz), 4.18 (dd, 1H, J=7.3, 4.8 Hz), 3.36(ddd, 1H, J=17.5, 8.8, 4.4 Hz), 2.93 (ddd, 1H, J=17.6, 8.3, 4.2 Hz),2.33 (m, 1H), 2.15 (m, 1H), 1.34 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ175.8, 144.2, 142.7, 132.6, 130.8, 130.7, 129.7, 128.1, 127.6, 127.4,57.8, 44.3, 31.1, 29.4, 22.8. HRMS calc for C₂₀H₂₁Cl₂NOS 394.0799. found394.0767.

The solution of imine (2) was cooled to −10° C. and 36.3 kg of a 0.5 Msolution of 9-borabicyclononane (9-BBN) in THF, was added slowly (over 3h) and the mixture was stirred at 0° C. until reaction completion. A 4NHCl/methanol (8 L) was added to the mixture and stirred until thehydrolysis reaction was complete. After neutralization with about 15 kgof 6N aqueous NaOH (pH 8), the mixture was distilled to remove THF andmethanol. The residue (aqueous phase) was extracted twice with methylt-butyl ether (2×16 L). The organic phase was then washed with water.The organic phase was concentrated, then cooled to 0° C. followed byaddition of 2N HCl in methyl t-butyl ether (5.4 kg). The productprecipitated as the HCl salt. The slurry was filtered, washed withmethyl t-butyl ether (2×8 L) and dried under vacuum at 45° C. to affordabout 3.73 kg of crude(1R,4S)-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamineHCl (compound P). A purified sample of P was analyzed: m.p. 152-154° C.,¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.58 (d, 1H, J=7.7 Hz), 7.29 (m, 2H),7.18 (br. t, 1H, J=7.5 Hz), 7.09 (d, 1H, J=1.8 Hz), 6.87 (d, 1H, J=7.7Hz), 6.80 (dd, 1H, J=8.3, 2.0 Hz), 4.65 (dd, 1H, J=4.4, 4.4 Hz), 4.15(t, 1H, J=5.5 Hz), 3.30 (d, 1H, J=3.7 Hz), 2.35 (m, 1H), 1.95 (m, 1H),1.85 (m, 1H), 1.75 (m, 1H), 1.23 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ147.1, 138.4, 138.0, 132.6, 130.8, 130.6, 130.5, 129.8, 128.3, 127.9,55.8, 53.3, 44.0, 28.2, 27.7, 22.9. HRMS calc for C₂₀H₂₃Cl₂NOS 396.0956.found 396.0968.

The crude(1R,4S)-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamineHCl (3.63 kg) was charged to a suitable reactor and 128 L of denaturedethanol was added. The mixture was stirred at reflux and polishfiltered. The volume was reduced to about 50% via distillation, and thencooled to 50° C. 80 L of heptane was added to the slurry to complete theproduct crystallization and then the slurry was cooled to −5° C. Theproduct was filtered, the cake was washed twice with 5.7 L ofethanol/heptane (1/1 v/v) and then washed with 6 L of hexane. The wetcake was dried under vacuum at about 45° C. to afford 2.57 kg ofproduct. The product had a chemical purity of 99.65 A % and adiastereomeric purity in excess of 99%.

Thus, the invention is also directed to a novel method of preparation ofcompound P as a free base or as an acid addition salt. In oneembodiment, the process for preparation of compound P

comprises:

-   -   a) reacting a compound of formula 1

-   -   -   wherein Z is chosen from aryl, aryl substituted by alkyl,            alkyl substituted by aryl, and —CR⁴R⁵R⁶, wherein R⁴ is C₁-C₆            alkyl, R⁵ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl,        -   in presence of a dehydrating agent to obtain compound of            formula 2a

-   -   -    and

    -   b) reducing the compound of formula 2a with a hydride reducing        agent followed by solvolysis.

In one embodiment, Z is tert-butyl, wherein each of R⁴, R⁵, and R⁶ ismethyl.

In one embodiment, the solvolysis is catalyzed by acid. In an optionalfurther step, the process further comprises crystallizing an acidaddition salt of the compound of formula P.

In another embodiment, the process further involves recrystallizing anacid addition salt of the compound of formula P from a solvent selectedfrom an alcohol and a mixture of alcohol and hydrocarbon solvent. Anexample of hydrocarbon solvent is toluene.

At any point, when an acid addition salt of compound P is obtained, afurther step may be performed of converting of an acid addition salt toa free base of compound P. The converting step may comprise treatingwith a base.

The dehydrating agent may be selected from titanium alkoxide, borontrifluoride etherate, boron trifluoride etherate with magnesium sulfate,and molecular sieves. The titanium alkoxide may be selected fromtitanium ethoxide and titanium isopropoxide.

The reducing agent may selected from 9-borabicyclononane, sodiumborohydride, catechol borane, borane, and diisobutylaluminum hydridewith zinc halide. The reducing step may be carried out in a solventcomprising tetrahydrofuran.

The acid that may be used in the solvolysis step may be a hydrochloricacid. The solvolysis step may be a hydrolysis reaction, or may beperformed under non-aqueous conditions, for example, by use ofmethanol/acid mixture.

The compounds P and Q were tested for their inhibition of functionaluptake of serotonin (5-HT), norepinephrine (NE), or dopamine (DA), insynaptosomes prepared from rat whole brain, hypothalamus, or corpusstriatum, respectively. Compounds were tested initially at 10 μA induplicate, and if ≧50% inhibition of uptake was observed, they weretested further at 10 different concentrations in duplicate in order toobtain full inhibition curves. IC₅₀ values (concentration inhibitingcontrol activity by 50%) were then determined by nonlinear regressionanalysis of the inhibition curves and tabulated below in the Examplessection.

Combination Therapy

One aspect of the present invention relates to combination therapy. Thistype of therapy is advantageous because the co-administration of activeingredients achieves a therapeutic effect that is greater than thetherapeutic effect achieved by administration of only a singletherapeutic agent. In one embodiment, the co-administration of two ormore therapeutic agents achieves a synergistic effect, i.e., atherapeutic affect that is greater than the sum of the therapeuticeffects of the individual components of the combination. In anotherembodiment, the co-administration of two or more therapeutic agentsachieves an augmentation effect.

The active ingredients that comprise a combination therapy may beadministered together via a single dosage form or by separateadministration of each active agent. In certain embodiments, the firstand second therapeutic agents are administered in a single dosage form.The agents may be formulated into a single tablet, pill, capsule, orsolution for parenteral administration and the like.

Alternatively, the first therapeutic agent and the second therapeuticagents may be administered as separate compositions, e.g., as separatetablets or solutions. The first active agent may be administered at thesame time as the second active agent or the first active agent may beadministered intermittently with the second active agent. The length oftime between administration of the first and second therapeutic agentmay be adjusted to achieve the desired therapeutic effect. In certaininstances, the second therapeutic agent may be administered only a fewminutes (e.g., 1, 2, 5, 10, 30, or 60 min) after administration of thefirst therapeutic agent. Alternatively, the second therapeutic agent maybe administered several hours (e.g., 2, 4, 6, 10, 12, 24, or 36 hr)after administration of the first therapeutic agent. In certainembodiments, it may be advantageous to administer more than one dosageof the second therapeutic agent between administrations of the firsttherapeutic agent. For example, the second therapeutic agent may beadministered at 2 hours and then again at 10 hours followingadministration of the first therapeutic agent. Alternatively, it may beadvantageous to administer more than one dosage of the first therapeuticagent between administrations of the second therapeutic agent.Importantly, it is preferred that the therapeutic effects of each activeingredient overlap for at least a portion of the duration of eachtherapeutic agent so that the overall therapeutic effect of thecombination therapy is attributable in part to the combined orsynergistic effects of the combination therapy.

The dosage of the active agents will generally be dependent upon anumber of factors including pharmacodynamic characteristics of eachagent of the combination, mode and route of administration of activeagent(s), the health of the patient being treated, the extent oftreatment desired, the nature and kind of concurrent therapy, if any,and the frequency of treatment and the nature of the effect desired. Ingeneral, dosage ranges of the active agents often range from about 0.001to about 250 mg/kg body weight per day. For example, for a normal adulthaving a body weight of about 70 kg, a dosage in the range of from about0.1 to about 25 mg/kg body weight is typically preferred. However, somevariability in this general dosage range may be required depending uponthe age and weight of the subject being treated, the intended route ofadministration, the particular agent being administered and the like.Since two or more different active agents are being used together in acombination therapy, the potency of each agent and the interactiveeffects achieved using them together must be considered. Importantly,the determination of dosage ranges and optimal dosages for a particularmammal is also well within the ability of one of ordinary skill in theart having the benefit of the instant disclosure.

In certain embodiments, it may be advantageous for the pharmaceuticalcombination to have a relatively large amount of the first componentcompared to the second component. In certain instances, the ratio of thefirst active agent to second active agent is 30:1, 20:1, 15:1, 10:1,9:1, 8:1, 7:1, 6:1, or 5:1. In certain embodiments, it may be preferableto have a more equal distribution of pharmaceutical agents. In certaininstances, the ratio of the first active agent to the second activeagent is 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, or 1:4. In certain embodiments,it may be advantageous for the pharmaceutical combination to have arelatively large amount of the second component compared to the firstcomponent. In certain instances, the ratio of the second active agent tothe first active agent is 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or5:1. Importantly, a composition comprising any of the above-identifiedcombinations of first therapeutic agent and second therapeutic agent maybe administered in divided doses 1, 2, 3, 4, 5, 6, or more times per dayor in a form that will provide a rate of release effective to attain thedesired results. In a preferred embodiment, the dosage form containsboth the first and second active agents. In a more preferred embodiment,the dosage form only has to be administered one time per day and thedosage form contains both the first and second active agents.

For example, a formulation intended for oral administration to humansmay contain from 0.1 mg to 5 g of the first therapeutic agent and 0.1 mgto 5 g of the second therapeutic agent, both of which are compoundedwith an appropriate and convenient amount of carrier material varyingfrom about 5 to about 95 percent of the total composition. Unit dosageswill generally contain between from about 0.5 mg to about 1500 mg of thefirst therapeutic agent and 0.5 mg to about 1500 mg of the secondtherapeutic agent. In a preferred embodiment, the dosage comprises 0.5mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg,300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, etc., up to 1500 mgof the first therapeutic agent. In a preferred embodiment, the dosagecomprises 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, etc., upto 1500 mg of the second therapeutic agent. The optimal ratios of thefirst and second therapeutic agent can be determined by standard assaysknown in the art.

The toxicity and therapeutic efficacy of compositions of the inventioncan be determined by standard pharmaceutical procedures in cell culturesor experimental animals, e.g., for determining the LD₅₀ (the dose lethalto 50% of the population) and the ED₅₀ (the dose therapeuticallyeffective in 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index and it can be expressed asthe ratio LD₅₀/ED₅₀. Compounds which exhibit large therapeutic indicesare preferred. The data obtained from these cell culture assays andanimal studies can be used in formulating a range of dosage for use inhumans. The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. For anycompound used in the method of the invention, the therapeuticallyeffective dose can be estimated initially from cell culture assays. Adose may be formulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of RTproduction from infected cells compared to untreated control asdetermined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography (HPLC).

Synergism and Augmentation

The term “synergistic” refers to a combination which is more effectivethan the additive effects of any two or more single agents. Asynergistic effect permits the effective treatment of a disease usinglower amounts (doses) of either individual therapy. The lower dosesresult in lower toxicity without reduced efficacy. In addition, asynergistic effect can result in improved efficacy, e.g., improvedantidepressant activity. Finally, synergy may result in an improvedavoidance or reduction of disease as compared to any single therapy.

Combination therapy can allow for the use of lower doses of the firsttherapeutic or the second therapeutic agent (referred to as “apparentone-way synergy” herein), or lower doses of both therapeutic agents(referred to as “two-way synergy” herein) than would normally berequired when either drug is used alone.

In certain embodiments, the synergism exhibited between the secondtherapeutic agent and the first therapeutic agent is such that thedosage of the first therapeutic agent would be sub-therapeutic ifadministered without the dosage of the second therapeutic agent.Alternatively, the synergism exhibited between the second therapeuticagent and the first therapeutic agent is such that the dosage of thesecond therapeutic agent would be sub-therapeutic if administeredwithout the dosage of the first therapeutic agent.

The terms “augmentation” or “augment” refer to combination where one ofthe compounds increases or enhances therapeutic effects of anothercompound or compounds administered to a patient. In some instances,augmentation can result in improving the efficacy, tolerability, orsafety, or any combination thereof, of a particular therapy.

In certain embodiments, the present invention relates to apharmaceutical composition comprising a therapeutically effective doseof a first therapeutic agent together with a dose of a secondtherapeutic agent effective to augment the therapeutic effect of thefirst therapeutic agent. In other embodiments, the present inventionrelates to methods of augmenting the therapeutic effect in a patient ofa first therapeutic agent by administering the second therapeutic agentto the patient. In other embodiments, the present invention relates to apharmaceutical composition comprising an therapeutically effective doseof a second therapeutic agent together with a dose of a firsttherapeutic agent effective to augment the therapeutic effect of thesecond therapeutic agent. In other embodiments, the present inventionrelates to methods of augmenting the therapeutic effect in a patient ofa second therapeutic agent by administering the first therapeutic agentto the patient.

In certain preferred embodiments, the invention is directed in part tosynergistic combinations of the first therapeutic agent in an amountsufficient to render a therapeutic effect together with a secondtherapeutic agent. For example, in certain embodiments a therapeuticeffect is attained which is at least about 2 (or at least about 4, 6, 8,or 10) times greater than that obtained with the dose of the firsttherapeutic agent alone. In certain embodiments, the synergisticcombination provides a therapeutic effect which is up to about 20, 30 or40 times greater than that obtained with the dose of first therapeuticagent alone. In such embodiments, the synergistic combinations displaywhat is referred to herein as an “apparent one-way synergy”, meaningthat the dose of second therapeutic agent synergistically potentiatesthe effect of the first therapeutic agent, but the dose of firsttherapeutic agent does not appear to significantly potentiate the effectof the second therapeutic agent.

In certain embodiments, the combination of active agents exhibit two-waysynergism, meaning that the second therapeutic agent potentiates theeffect of the first therapeutic agent, and the first therapeutic agentpotentiates the effect of the second therapeutic agent. Thus, otherembodiments of the invention relate to combinations of a secondtherapeutic agent and a first therapeutic agent where the dose of eachdrug is reduced due to the synergism between the drugs, and thetherapeutic effect derived from the combination of drugs in reduceddoses is enhanced. The two-way synergism is not always readily apparentin actual dosages due to the potency ratio of the first therapeuticagent to the second therapeutic agent. For instance, two-way synergismcan be difficult to detect when one therapeutic agent displays muchgreater therapeutic potency relative to the other therapeutic agent.

The synergistic effects of combination therapy may be evaluated bybiological activity assays. For example, the therapeutic agents are bemixed at molar ratios designed to give approximately equipotenttherapeutic effects based on the EC₉₀ values. Then, three differentmolar ratios are used for each combination to allow for variability inthe estimates of relative potency. These molar ratios are maintainedthroughout the dilution series. The corresponding monotherapies are alsoevaluated in parallel to the combination treatments using the standardprimary assay format. A comparison of the therapeutic effect of thecombination treatment to the therapeutic effect of the monotherapy givesa measure of the synergistic effect. Further details on the design ofcombination analyses can be found in B E Korba (1996) Antiviral Res.29:49. Analysis of synergism, additivity, or antagonism can bedetermined by analysis of the aforementioned data using the CalcuSyn™program (Biosoft, Inc.). This program evaluates drug interactions by useof the widely accepted method of Chou and Talalay combined with astatistically evaluation using the Monte Carlo statistical package. Thedata are displayed in several different formats including median-effectand dose-effects plots, isobolograms, and combination index [CI] plotswith standard deviations. For the latter analysis, a CI greater than 1.0indicates antagonism and a CI less than 1.0 indicates synergism.

Compositions of the invention present the opportunity for obtainingrelief from moderate to severe cases of disease. Due to the synergisticand/or additive effects provided by the inventive combination of thefirst and second therapeutic agent, it may be possible to use reduceddosages of each of therapeutic agent. By using lesser amounts of otheror both drugs, the side effects associated with each may be reduced innumber and degree. Moreover, the inventive combination avoids sideeffects to which some patients are particularly sensitive.

FORMULATIONS AND DEFINITIONS

Pharmaceutical compositions of the present invention may be administeredby any suitable route of administration that provides a patient with atherapeutically effective dosage of the active ingredients. Typically,the pharmaceutical compositions described herein will be formulated fororal administration or for inhalation. Suitable dosage forms includetablets, troches, cachets, caplets, capsules, including hard and softgelatin capsules, and the like. Tablet forms, however, remain apreferred dosage form because of advantages afforded both the patient(e.g., accuracy of dosage, compactness, portability, blandness of tasteand ease of administration) and to the manufacturer (e.g., simplicityand economy of preparation, stability and convenience in packaging,shipping and dispensing).

The pharmaceutical compositions may further include a “pharmaceuticallyacceptable inert carrier” and this expression is intended to include oneor more inert excipients, which include starches, polyols, granulatingagents, microcrystalline cellulose, diluents, lubricants, binders,disintegrating agents, and the like. If desired, tablet dosages of thedisclosed compositions may be coated by standard aqueous or nonaqueoustechniques. In one embodiment, coating with hydroxypropylmethylcellulose(HPMC) is employed. “Pharmaceutically acceptable carrier” alsoencompasses controlled release means. Compositions of the presentinvention may also optionally include other therapeutic ingredients,anti-caking agents, preservatives, sweetening agents, colorants,flavors, desiccants, plasticizers, dyes, and the like. However, any suchoptional ingredient must be compatible with combination of activeingredients to insure the stability of the formulation.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids and bases and organic acids and bases. When thecompounds of the present invention are basic, salts may be prepared frompharmaceutically acceptable non-toxic acids including inorganic andorganic acids. Suitable pharmaceutically acceptable acid addition saltsfor the compounds of the present invention include acetic,benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaricacid, p-toluenesulfonic, and the like. When the compounds contain anacidic side chain, suitable pharmaceutically acceptable base additionsalts for the compounds of the present invention include metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. In one embodiment, eszopiclone isformulated as a succinate salt. In another embodiment, eszopiclone isformulated as a fumarate salt.

Eszopiclone, trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, andtrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine arechiral compounds that can exist as a racemic mixture, a non-equalmixture of enantiomers, or as a single enantiomer. Importantly, therecitation of a compound that can exist as a racemic mixture, anon-equal mixture of enantiomers, or a single enantiomer is meant toencompass all three aforementioned forms, unless stated otherwise. Theterm “enantiomeric excess” is well known in the art and is defined for aresolution of ab into a+b as:

${ee}_{a} = {\left( \frac{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} - {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}}{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} + {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}} \right) \times 100}$

The term “enantiomeric excess” is related to the older term “opticalpurity” in that both are measures of the same phenomenon. The value ofe.e. will be a number from 0 to 100, zero being racemic and 100 beingpure, single enantiomer. A compound which in the past might have beencalled 98% optically pure is now more precisely described as 96% e.e.;in other words, a 90% e.e. reflects the presence of 95% of oneenantiomer and 5% of the other in the material in question. In instanceswhen a specific enantiomer is recited (e.g., eszopiclone) for use in thecompositions or methods of the present invention, this indicates thatthe composition contains a significantly greater proportion of thespecified enantiomer in relation to the non-specified enantiomer. In apreferred embodiment, compositions comprising a specified enantiomercontain the specified enantiomer in at least 90% e.e. More preferably,such compositions comprising a specified enantiomer contain thespecified enantiomer in at least 95% e.e. Even more preferably, suchcompositions comprising a specified enantiomer contain the specifiedenantiomer in at least 98% e.e. Most preferably, such compositionscomprising a specified enantiomer contain the specified enantiomer in atleast 99% e.e.

For example, compositions comprising eszopiclone contain theS-enantiomer of zopiclone in at least 90% e.e. More preferably,compositions comprising eszopiclone contain the S-enantiomer ofzopiclone in at least 95% e.e. Even more preferably, such compositionscomprising eszopiclone contain the S-enantiomer of zopiclone in at least98% e.e. Most preferably, such compositions comprising eszopiclonecontain the S-enantiomer of zopiclone in at least 99% e.e.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr, J.Chem. Ed., 62:114-120 (1985): solid and broken wedges are used to denotethe absolute configuration of a chiral element; wavy lines indicatedisavowal of any stereochemical implication which the bond it representscould generate; solid and broken bold lines are geometric descriptorsindicating the relative configuration shown but not implying anyabsolute stereochemistry; and wedge outlines and dotted or broken linesdenote enantiomerically pure compounds of indeterminate absoluteconfiguration.

The term “antagonist” refers to a compound that binds to a receptorbinding site, but does not activate the receptor, a compound that bindsto a receptor and blocks receptor binding site, or a compound that bindsto an allosteric site on a receptor (non-competitive antagonist)resulting in prevention of activation of the receptor by its ligand. Theresulting inhibition of the receptor may vary in degree and duration.

The term “patient” refers to a mammal in need of a particular treatment.In a preferred embodiment, a patient is a primate, canine, feline, orequine. In another preferred embodiment, a patient is a human.

The terms “co-administration” and “co-administering” refer to bothconcurrent administration (administration of two or more therapeuticagents at the same time) and time varied administration (administrationof one or more therapeutic agents at a time different from that of theadministration of an additional therapeutic agent or agents), as long asthe therapeutic agents are present in the patient to some extent at thesame time.

The term “solvate” refers to a pharmaceutically acceptable form of aspecified compound, with one or more solvent molecules, that retains thebiological effectiveness of such compound. Examples of solvates includecompounds of the invention in combination with solvents such, forexample, water (to form the hydrate), isopropanol, ethanol, methanol,dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, oracetone. Also included are formulations of solvate mixtures such as acompound of the invention in combination with two or more solvents.

The term “disorders” as used herein includes menopause, perimenopause,mood disorders, anxiety disorders, and cognitive disorders.

The term “menopause” as used herein includes various symptoms ofmenopause and perimenopause, such as hot flashes, awakenings due to hotflashes, nocturnal awakenings, and mood disorders associated withmenopause or perimenopause, such as depression and anxiety.

The term “mood disorder” as used herein includes major depression, majordepressive disorder, mild depression, severe depression withoutpsychosis, severe depression with psychosis, melancholia (formerlyendogenous depression), atypical depression, dysthymic disorder, manicdepression, bipolar disorder, bipolar I disorder, bipolar II disorder,bipolar III disorder, cyclothymic disorder, and chronic hypomania.

The term “mood disorder” as used herein also includes premenstrualsyndrome (PMS), premenstrual dysphoric disorder (PMDD), prenataldepression, and postpartum depression.

The term “anxiety disorder” as used herein refers to panic attacks,panic disorder, phobic disorders (such as agoraphobia, specific phobias,social phobia, avoidant personality disorder), obsessive-compulsivedisorder (OCD), posttraumatic stress disorder, acute stress disorder,and generalized Anxiety Disorder.

The term “cognitive disorder” as used herein refers to delirium (acuteconfusional state), dementia, Alzheimer's Disease, Lewy body dementia,vascular dementia, Binswanger's dementia (subcortical arterioscleroticencephalopathy), Parkinson's disease, progressive supranuclear palsy,Huntington's disease (chorea), Pick's disease, Klüver-Bucy syndrome,frontal lobe dementia syndromes, normal-pressure hydrocephalus, subduralhematoma, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinkerdisease, general paresis, and AIDS dementia. The term “cognitivedisorder” as used herein also includes decreased cognitive function andmemory loss.

The term “treating” when used in connection with the disorders meansamelioration, prevention or relief from the symptoms and/or effectsassociated with these disorders and includes the prophylacticadministration of the compositions of the invention, or pharmaceuticallyacceptable salt thereof, to substantially diminish the likelihood orseriousness of the condition.

The invention now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

EXAMPLES Example 1 Formulations

The following formulations are exemplary of eszopiclone and trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine ortrans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenaminecombination tablet or capsule formulations:

TABLE 1 Eszopiclone and trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N- methyl-1-napthalenaminecompositions Combo Strengths (Eszopiclone/trans 4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydro-N-methyl-1- Ingredientnapthalenamine, mg/unit) (Tablet and Capsule) 3.0/25.0 3.0/50.03.0/100.0 Eszopiclone 3.00 3.00 3.00 trans4-(3,4-dichlorophenyl)-1,2,3,4- 28.00 56.00 112.00tetrahydro-N-methyl-1- napthalenamine HCl¹ Microcrystalline Cellulose,NF (Avicel ® 198.90 198.90 198.90 PH102) Dibasic Calcium PhosphateAnhydrous 90.00 90.00 90.00 USP Croscarmellose Sodium, NF 6.00 6.00 6.00Colloidal Silicon Dioxide, NF 0.60 0.60 0.60 Magnesium Stearate, NF 1.501.50 1.50 Total tablet wt. or capsule fill wt. 328.00 356.00 412.00Empty Size 0 hard gelatin capsule wt. 90.00 90.00 90.00 Total weight offilled capsule 418.00 446.00 502.00 ¹trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine HClpotency is expressed in terms of free base. 1.12 mg trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine HClis equivalent to 1.00 mg of free base.

TABLE 2 Eszopiclone and trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- napthalenamine compositionsCombo Strengths (Eszopiclone/trans 4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, Ingredient mg/unit) (Tablet and Capsule)3.0/25.0 3.0/50.0 3.0/100.0 Eszopiclone 3.00 3.00 3.00 trans4-(3,4-dichlorophenyl)-1,2,3,4- 28.00 56.00 112.00tetrahydro-1-napthalenamine HCl¹ Microcrystalline Cellulose, NF(Avicel ® 198.90 198.90 198.90 PH102) Dibasic Calcium PhosphateAnhydrous 90.00 90.00 90.00 USP Croscarmellose Sodium, NF 6.00 6.00 6.00Colloidal Silicon Dioxide, NF 0.60 0.60 0.60 Magnesium Stearate, NF 1.501.50 1.50 Total tablet wt. or capsule fill wt. 328.00 356.00 412.00Empty Size 0 hard gelatin capsule wt. 90.00 90.00 90.00 Total weight offilled capsule 418.00 446.00 502.00 ¹trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl potencyis expressed in terms of free base. 1.12 mg trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl isequivalent to 1.00 mg of free base.

The above-presented formulations may be prepared by performing thefollowing steps:

-   1. Screen eszopiclone through 80 mesh.-   2. Screen trans    4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine    or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine    through 40 mesh.-   3. Screen remaining ingredients through #20 or #30 mesh screen.-   4. Blend eszopiclone with a portion of MCC (microcrystalline    cellulose).-   5. Blend trans    4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine    or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine    with the blend from Step 4.-   6. Blend the mixture from Step 5 with remaining MCC in three steps.-   7. Blend mixture from Step 6 with dicalcium phosphate.-   8. Mix croscarmellose with silicon dioxide, then blend with the    mixture from Step 7.-   9. Blend mixture from Step 8 with magnesium stearate.-   10. For tablets, compress on a suitable tablet press machine.-   11. For capsules, fill into Size 0 hard gelatin capsules on a    suitable capsule filling machine.-   12. For tablets, coat the tablet cores from Step 10 with Opadry II    in a suitable conventional tablet coating machine.

Example 2 Clinical Study on Treatment of Menopause or Perimenopause withEszopiclone

The study was aimed at observing efficacy of eszopiclone 3 mg comparedto placebo in the treatment of insomnia secondary to perimenopause ormenopause.

The study was a multicenter, randomized, double-blind,placebo-controlled, parallel-group study. The study had a one-weeksingle-blind placebo run-in period, followed by four weeks of doubleblind treatment, and one week of single blind placebo wash-out. Theprimary method of analysis compared the post-randomization resultsbetween the two treatment groups.

Subjects were women with insomnia secondary to perimenopause ormenopause. Subjects were perimenopausal or menopausal and had insomniasymptoms including ≧45 minutes sleep latency (SL) and total sleep time(TST) ≦6 hours. Perimenopausal/menopausal symptoms predated the onset ofsleep disturbance symptoms. The patient population was predominatelyCaucasian (77.2%). The mean age was 49, with a range of 40-60.

A total of 410 subjects were randomized. Among them, 201 received 3 mgof eszopiclone (ESZ) nightly (at bedtime) for four weeks and 209received matching placebo (PBO). The discontinuation rates weremoderate, 11.9% in the ESZ group and 12.9% in the PBO group.

The ESZ group had significantly fewer nocturnal awakenings due to hotflashes during Week 1 compared with PBO (LS means of 0.3 and 0.5 pernight for ESZ and PBO, respectively; p=0.0016). This effect was notsignificant for the other weeks, but was marginally significant for theDB average (p=0.059). When change from baseline was analyzed, ESZsignificantly reduced the number of nocturnal awakenings due to hotflashes in Week 1 compared with PBO (p<0.0001). The difference was notsignificant for Week 2, but was marginally significant for Weeks 3 and 4(p=0.094 and 0.055, respectively) and was significant for the DB average(p=0.0045). See Table 3.

TABLE 3 Number of Nocturnal Awakenings due to Hot Flashes(Intent-to-Treat Population) Placebo Eszopiclone 3 mg Time ObservedChange from Observed Change from Point Statistic Value Baseline [1]Value Baseline [1] Baseline N 171 150 Mean (SD) 1.1 (1.2) 1.3 (1.2) 25thPercentile 0.0 0.3 Median 1.0 1.0 75th Percentile 1.5 2.0 Minimum,Maximum  0.0, 10.0 0.0, 6.0 Week 1 N 179 157 175 140 Mean (SD) 0.8 (1.0)−0.2 (0.9) 0.5 (0.7) −0.7 (1.0) 25th Percentile 0.0 −0.7 0.0 −1.2 Median0.5 0.0 0.2 −0.5 75th Percentile 1.3 0.2 1.0 0.0 Minimum, Maximum 0.0,5.0 −5.0, 2.3 0.0, 3.0 −6.0, 0.8 Least Squares Means (SE) 0.8 (0.1) 0.5(0.1) [2] p-value vs. placebo [2] <.0001 Least Squares Means (SE) −0.3(0.1) −0.7 (0.1) [3] p-value vs. placebo [3] <.0001 Week 2 N 174 153 170139 Mean (SD) 0.6 (0.8) −0.5 (1.0) 0.5 (0.7) −0.7 (1.0) 25th Percentile0.0 −1.0 0.0 −1.0 Median 0.3 −0.4 0.0 −0.6 75th Percentile 1.0 0.0 1.00.0 Minimum, Maximum 0.0, 4.3 −6.8, 1.3 0.0, 3.0 −6.0, 2.0 Least SquaresMeans (SE) 0.6 (0.1) 0.5 (0.1) [2] p-value vs. placebo [2] 0.2137 LeastSquares Means (SE) −0.5 (0.1) −0.6 (0.1) [3] p-value vs. placebo [3]0.1963 Week 3 N 162 147 164 129 Mean (SD) 0.6 (0.8) −0.5 (1.0) 0.5 (0.7)−0.7 (1.1) 25th Percentile 0.0 −0.8 0.0 −1.0 Median 0.3 −0.3 0.0 −0.475th Percentile 1.0 0.0 1.0 0.0 Minimum, Maximum 0.0, 4.6 −6.2, 2.7 0.0,3.0 −6.0, 1.5 Least Squares Means (SE) 0.6 (0.1) 0.5 (0.1) [2] p-valuevs. placebo [2] 0.1583 Least Squares Means (SE) −0.5 (0.1) −0.6 (0.1)[3] p-value vs. placebo [3] 0.2408 Week 4 N 151 135 154 121 Mean (SD)0.6 (0.9) −0.5 (1.0) 0.4 (0.7) −0.8 (1.2) 25th Percentile 0.0 −1.0 0.0−1.3 Median 0.0 −0.3 0.0 −0.7 75th Percentile 1.0 0.0 1.0 0.0 Minimum,Maximum 0.0, 5.3 −4.8, 4.0 0.0, 3.6 −6.0, 2.1 Least Squares Means (SE)0.6 (0.1) 0.4 (0.1) [2] p-value vs. placebo [2] 0.0786 Least SquaresMeans (SE) −0.5 (0.1) −0.7 (0.1) [3] p-value vs. placebo [3] 0.0683 DB N192 165 188 146 Average Mean (SD) 0.7 (0.8) −0.4 (0.9) 0.5 (0.6) −0.7(1.0) 25th Percentile 0.0 −0.8 0.0 −1.1 Median 0.4 −0.2 0.2 −0.5 75thPercentile 1.0 0.0 0.9 0.0 Minimum, Maximum 0.0, 4.6 −6.0, 1.5 0.0, 2.7−6.0, 1.5 Least Squares Means (SE) 0.7 (0.1) 0.5 (0.1) [2] p-value vs.placebo [2] 0.0057 Least Squares Means (SE) −0.4 (0.0) −0.7 (0.1) [3]p-value vs. placebo [3] 0.0016 [1] Week 1 = First week of double-blindtreatment, Week 2 = Second week of double-blind treatment, etc. DBAverage includes all scheduled assessments obtained after Visit 3 up toand including Visit 5. Baseline is the average of all pre-DBobservations. [2] The pairwise comparison is a two-sided test performedusing an ANOVA model, using the MIXED procedure with treatment and siteas fixed effects. [3] The pairwise comparison is a two-sided testperformed using an ANCOVA model, using the MIXED procedure withtreatment and site as fixed effects and baseline as the covariate.

A Physician Global Assessment was administered at Week 4, the end of thedouble-blind treatment period. ESZ patients had significantly betterscores at this time compared with PBO (LS means of 2.7 and 3.3 for ESZand PBO, respectively; p<0.0001). See Table 4.

TABLE 4 Menopause and Perimenopause Study, Physician Global Assessment(Intent-to-Treat Population) Placebo Eszopiclone 3 mg Observed Changefrom Observed Change from Visit (Week) Statistic Value Baseline ValueBaseline 3 (Baseline) N 202 195 Mean (SD) 3.6 (1.0) 3.7 (1.0) 25thPercentile 3.0 4.0 Median 4.0 4.0 75th Percentile 4.0 4.0 Minimum,Maximum 0.0, 6.0 0.0, 7.0 5 (Week 4) N 191 188 189 185 Mean (SD) 3.3(1.1) −0.3 (1.4) 2.6 (1.2) −1.0 (1.4) 25th Percentile 2.0 −1.0 2.0 −2.0Median 4.0 0.0 2.0 −1.0 75th Percentile 4.0 0.0 4.0 0.0 Minimum, Maximum1.0, 6.0 −4.0, 5.0 1.0, 6.0 −4.0, 6.0 Least Squares Means 3.3 (0.1) 2.7(0.1) (SE) [1] p-value vs. placebo [1] <.0001 Least Squares Means −0.3(0.1) −0.9 (0.1) (SE) [2] p-value vs. placebo [2] <.0001 [1] Thepairwise comparison is a two-sided test performed using an ANOVA model,using the MIXED procedure with treatment and site as fixed effects. [2]The pairwise comparison is a two-sided test performed using an ANCOVAmodel, using the MIXED procedure with treatment and site as fixedeffects and baseline as the covariate. Note(s): The responses to theassessment question: Overall the subject's perimenopausal or menopausalsymptoms since the last assessment are: 0 = Not assessed, 1 = Very muchimproved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 =Minimally worse, 6 = Much worse, 7 = Very much worse.

The results of the study will change slightly because data from onesite, consisting of 11 of the 410 subjects analyzed above will beexcluded due to negative findings during a site audit. It is expectedthat the conclusions of the study will not change after exclusion ofthese 11 subjects.

Example 3 trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamineActivity Assays Experimental Conditions for Monoamine Uptake AssaysSerotonin Functional Uptake Assay

Characterization of serotonin uptake is performed using synaptosomesisolated in a 0.32 M sucrose buffer from a male Wistar rat cortex. Theuptake of radiolabelled serotonin by synaptosomes (100 μg ofproteins/point) is allowed by incubating them in a deep well for 15minutes at 37° C. in presence of test compounds and[3H]5-hydroxytryptamin (0.1 μCi/point).

Synaptosomes and [³H]5-hydroxytryptamine are prepared in a Krebs bufferpH 7.4 containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid.This incubation buffer is oxygenated during 5 minutes before incubation.Basal control is incubated for 15 minutes at 4° C. in order to avoid anyuptake. Following this incubation the uptake is stopped by filtrationthrough an “unifilter 96-wells GFB” Packard plate washed with Krebsbuffer containing 25 mM NaHCO₃ in order to eliminate the free[³H]5-hydroxytryptamine. The radioactivity associated to thesynaptosomes retained onto the unifilter corresponding to the uptake isthen measured with a microplate scintillation counter Topcount, Packardusing a scintillation liquid microscint 0, Packard.

The reference compound is imipramine tested at 10 concentrations rangingfrom 10⁻¹¹ M to 10⁻⁵ M in order to obtain an IC₅₀ value. See, Perovicsand Müller, “Pharmacological profile of hypericum extract: effect onserotonin uptake by postsynaptic receptors,” Arzeim. Forsch./Drug Res.,45:1145-1148 (1995).

Dopamine Functional Uptake Assay

Characterization of dopamine uptake is performed using synaptosomesisolated at Cerep in a 0.32 M sucrose buffer from a male Wistar ratstriatum. The uptake of radiolabelled dopamine by synaptosomes (20 μg ofproteins/point) is allowed by incubating them in a deep well for 15minutes at 37° C. in presence of test compounds and [³H]-dopamine (0.1μCi/point).

Synaptosomes and [³H]-dopamine are prepared in a Krebs buffer pH 7.4containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. Thisincubation buffer is oxygenated during 5 minutes before incubation.Basal control is incubated for 15 minutes at 4° C. in order to avoid anyuptake. Following this incubation the uptake is stopped by filtrationthrough an “unifilter 96-wells GFB” Packard plate washed with Krebsbuffer containing 25 mM NaHCO₃ in order to eliminate the free[³H]-dopamine. The radioactivity associated to the synaptosomes retainedonto the unifilter corresponding to the uptake is then measured with amicroplate scintillation counter Topcount, Packard using a scintillationliquid microscint 0, Packard. The reference compound is GRB12909 testedat 8 concentrations ranging from 10⁻¹¹ M to 10⁻⁶ M in order to obtain anIC₅₀ value. Jankowsky et al., “Characterization of sodium-dependent [³H]GBR-12935 binding in brain: a radioligand for selective labeling of thedopamine transport complex,” J. Neurochem., 46:1272-1276 (1986).

Norepinephrine Functional Uptake Assay

Characterization of norepinephrine uptake is performed usingsynaptosomes isolated at Cerep in a 0.32 M sucrose buffer from a maleWistar rat hypothalamus. The uptake of radiolabeled norepinephrine bysynaptosomes (100 μg of proteins/point) is allowed by incubating them ina deep well for 20 minutes at 37° C. in presence of test compounds and[³H]-norepinephrine (0.1 μCi/point).

Synaptosomes and [³H]-norepinephrine are prepared in a Krebs buffer pH7.4 containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. Thisincubation buffer is oxygenated during 5 minutes before incubation.Basal control is incubated for 20 minutes at 4° C. in order to avoid anyuptake. Following this incubation the uptake is stopped by filtrationthrough an “unifilter 96-wells GFB” Packard plate washed with Krebsbuffer containing 25 mM NaHCO₃ in order to eliminate the free[³H]-norepinephrine. The radioactivity associated to the synaptosomesretained onto the unifilter corresponding to the uptake is then measuredwith a microplate scintillation counter Topcount, Packard using ascintillation liquid microscint 0, Packard.

The reference compound is imipramine tested at 13 concentrations rangingfrom 10⁻¹¹ M to 10⁻⁵ M in order to obtain an IC₅₀ value. See, Perovicsand Müller, “Pharmacological profile of hypericum extract: effect onserotonin uptake by postsynaptic receptors,” Arzeim. Forsch./Drug Res.,45:1145-1148 (1995).

TABLE 5 IC₅₀ Values (μM) for Sertraline and Analogues in FunctionalMonoamine Uptakes Assays 5-HT NE DA sertraline 0.0016 0.31 0.048 (R,R)cis 0.11 0.11 0.039 A* 0.0075 0.012 0.0046 B** 0.33 0.024 0.026 A + B0.0070 0.0056 0.0073 imipramine 0.054/0.051 — — protriptyline — 0.0036 —GBR 12909 — — 0.0028/0.0051/0.0034 *A (1R,4S)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine **B(1S,4R)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine /separates multiple determinations — <50% inhibition

The IC₅₀ value for (R,R) had to be estimated because the lowest plateauof the inhibition curve (corresponding to 100% inhibition) was notreached at the highest concentration tested or 100% or control activitywas not apparent with the lowest concentration.

As shown in Table 5, A and B exhibit similar inhibitory potency on theneuronal uptake of NE, DA, and 5HT. Currently, the therapeutic approachto treating affective disorders in man is the selective inhibition of asingle monoamine uptake mechanism or the dual inhibition of two of thesemolecular targets. The equipotent inhibition of neuronal uptake of NE,DA and 5HT provides the clinician with the ability to more effectivelytreat the disorders mentioned specifically herein by elevating all ofthe monoamine levels in the brain simultaneously and over the samedose-range without the need to titrate separate drugs.

Example 4 trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine ActivityAssays

Monoamine uptake assays were performed according to protocols providedin Example 3 above. Results are tabulated below.

TABLE 6 IC₅₀ Values (μM) for Compounds of the Invention in FunctionalMonoamine Uptake Assays 5-HT NE DA sertraline 0.0016 0.31 0.048 P 0.00770.0096 0.0064 Q 0.088 0.035 0.019 P + Q 0.041 0.0088 0.0071 imipramine(standard) 0.054/0.051 — — protriptyline (standard) — 0.0036 — GBR 12909(standard) — — 0.0028/0.0051/0.0034 / separates multiple determinations— <50% inhibition

As shown in Table 6, P and Q exhibit similar inhibitory potency on theneuronal uptake of NE, DA, and 5HT. Currently, the therapeutic approachto treating affective disorders in man is the selective inhibition of asingle monoamine uptake mechanism or the dual inhibition of two of thesemolecular targets. The equipotent inhibition of the neuronal uptake ofNE, DA and 5HT provides the clinician with the ability to moreeffectively treat affective disorders and eating disorders by elevatingall of the monoamine levels in the brain simultaneously and over thesame dose-range without the need to titrate separate drugs. For thoseCNS disorders that are presently treated with dopaminergic,norepinephrine or mixed DA-NE uptake inhibitors (e.g. OCD, ADD, ADHD,sexual dysfunction and substance abuse), the equipotent inhibition ofthe neuronal uptake of NE, DA and 5HT provides more effective treatmentby adding the serotonergic effect.

Table 7 below presents data on effect of intraperitoneal administrationof (1R,4S)—N-[4-(3,4-dichlorophenyl-1,2,3,4-tetrahydro-1-naphthalenamine(Compound P) in the Behavioral Despair Test in mice.

TABLE 7 Effect of Intraperitoneal Administration of (1R,4S)-N-[4-(3,4-dichlorophenyl-1,2,3,4-tetrahydro-1naphthalenamine (P) in theBehavioral Despair Test¹ in Mice (N = 10) Imipramine P P P P P CompoundVehicle 10 mg/kg 0.03 mg/kg 0.1 mg/kg 0.3 mg/kg 1 mg/kg 3 mg/kgImmobility 130 63 128 119 114 29 12 Duration 82 28 120 96 109 66 49(sec) 129 33 96 85 115 87 0 172 89 129 100 93 34 3 162 85 99 103 23 5117 148 73 107 76 102 35 5 154 37 159 109 110 51 0 118 74 102 56 106 1940 133 95 115 98 98 81 0 153 5 122 62 120 50 26 Mean ± sem 138 58 118 9099 50 15 8 10 6 6 9 7 6 Dunnett P < 0.05 * ns * * * * ¹The BehavioralDespair Test is also known as the Porsolt swim test (Porsolt, et al.,1977. Nature 266: 730-732). ²Vehicle = saline * indicates a significantdifference vs vehicle for P < 0.05 (Dunnett test)

The contents of each of the references cited herein, including thecontents of the references cited within the primary references, areherein incorporated by reference in their entirety.

The invention being thus described, it is apparent that the same can bevaried in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications and equivalents as would be obvious to one skilled inthe art are intended to be included within the scope of the followingclaims.

1. A pharmaceutical composition comprising eszopiclone, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof, and trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, ora pharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof.
 2. A pharmaceutical composition comprisingeszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate,polymorph, or co-crystal thereof, and trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof.
 3. A method of treating a patient suffering from amenopause or perimenopause, comprising the step of co-administering to apatient in need thereof a therapeutically effective amount ofeszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate,polymorph, or co-crystal thereof, and a therapeutically effective amountof trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, ora pharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof.
 4. A method of treating a patient suffering from amenopause or perimenopause, comprising the step of co-administering to apatient in need thereof a therapeutically effective amount ofeszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate,polymorph, or co-crystal thereof, and a therapeutically effective amountof trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, ora pharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof.
 5. A method of treating a patient suffering from amood disorder, comprising the step of co-administering to a patient inneed thereof a therapeutically effective amount of eszopiclone, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof, and a therapeutically effective amount of trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, ora pharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof.
 6. A method of treating a patient suffering from amood disorder, comprising the step of co-administering to a patient inneed thereof a therapeutically effective amount of eszopiclone, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof, and a therapeutically effective amount of trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof.
 7. A method of treating a patient suffering from ananxiety disorder, comprising the step of co-administering to a patientin need thereof a therapeutically effective amount of eszopiclone, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof, and a therapeutically effective amount of trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, ora pharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof.
 8. A method of treating a patient suffering from ananxiety disorder, comprising the step of co-administering to a patientin need thereof a therapeutically effective amount of eszopiclone, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof, and a therapeutically effective amount of trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof.
 9. A method of treating a patient suffering from acognitive disorder, comprising the step of co-administering to a patientin need thereof a therapeutically effective amount of eszopiclone, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof, and a therapeutically effective amount of trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, ora pharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof.
 10. A method of treating a patient suffering from acognitive disorder, comprising the step of co-administering to a patientin need thereof a therapeutically effective amount of eszopiclone, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof, and a therapeutically effective amount of trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or apharmaceutically acceptable salt, solvate, clathrate, polymorph, orco-crystal thereof.
 11. The method according to claim 5 or 6, whereinthe mood disorder is selected from major depression, major depressivedisorder, mild depression, severe depression without psychosis, severedepression with psychosis, melancholia, atypical depression, dysthymicdisorder, manic depression, bipolar disorder, bipolar I disorder,bipolar II disorder, bipolar III disorder, cyclothymic disorder, chronichypomania, premenstrual syndrome, premenstrual dysphoric disorder,prenatal depression, and postpartum depression.
 12. The method accordingto claim 7 or 8, wherein the anxiety disorder is selected from panicattacks, panic disorder, phobic disorders, obsessive-compulsivedisorder, posttraumatic stress disorder, acute stress disorder, andgeneralized Anxiety Disorder.
 13. The method according to claim 9 or 10,wherein the cognitive disorder is selected from delirium, dementia,Alzheimer's Disease, Lewy body dementia, vascular dementia, Binswanger'sdementia, Parkinson's disease, progressive supranuclear palsy,Huntington's disease, Pick's disease, Klüver-Bucy syndrome, frontal lobedementia syndromes, normal-pressure hydrocephalus, subdural hematoma,Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease,general paresis, AIDS dementia, decreased cognitive function and memoryloss.
 14. A process for preparation of a compound of formula P

comprising: a) reacting a compound of formula 1

wherein Z is chosen from aryl, aryl substituted by alkyl, alkylsubstituted by aryl, and —CR⁴R⁵R⁶, wherein R⁴ is C₁-C₆ alkyl, R⁵ isC₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl, in presence of a dehydrating agentto obtain compound of formula 2a

 and b) reducing the compound of formula 2a with a hydride reducingagent followed by solvolysis.
 15. The process according to claim 14wherein solvolysis is catalyzed by acid.
 16. The process according toclaim 15 further comprising crystallizing an acid addition salt of thecompound of formula P.
 17. The process according to any of claims 14through 16 further comprising a step of converting a product compound toa free base of compound P.
 18. The process according to claim 14 whereinthe dehydrating agent is selected from titanium alkoxide, borontrifluoride etherate, boron trifluoride etherate with magnesium sulfate,and molecular sieves.
 19. The process according to claim 18 wherein thetitanium alkoxide is selected from titanium ethoxide and titaniumisopropoxide.
 20. The process according to claim 14 wherein the reducingagent is selected from 9-borabicyclononane, sodium borohydride, catecholborane, borane, and diisobutylaluminum hydride with zinc halide.
 21. Theprocess according to claim 15 wherein the acid is hydrochloric acid. 22.The process according to claim 14 wherein each of R⁴, R⁵, and R⁶ ismethyl.
 23. The process according to claim 17 wherein the convertingstep comprises treating with a base.
 24. The process according to claim16 further comprising recrystallizing an acid addition salt of thecompound of formula P from a solvent selected from an alcohol and amixture of alcohol and hydrocarbon solvent.
 25. The process according toclaim 20 wherein the reducing step is carried out in a solventcomprising tetrahydrofuran.